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A kind of glucagon-like peptide-1 analogue and its preparation method and application

A technology for glucagon and analogues, which is applied in the field of application of glucagon-like peptide-1 (GLP-1) analogues and dimers, drugs, and can solve the problems of drug compliance that needs to be improved , to achieve the effects of improving clinical application compliance, avoiding safety risks, and overcoming short half-life

Active Publication Date: 2019-12-17
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many attempts have been made over the years, only liraglutide has been developed and marketed based on the parent peptide chain of GLP-1 (7-36,7-37) so far.
Although liraglutide greatly prolongs the half-life of GLP-1 in vivo, it still needs to be injected once a day, and the medication compliance still needs to be improved

Method used

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  • A kind of glucagon-like peptide-1 analogue and its preparation method and application
  • A kind of glucagon-like peptide-1 analogue and its preparation method and application
  • A kind of glucagon-like peptide-1 analogue and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 Preparation of GLP-1 analogue monomer and dimer

[0051] A. Preparation of GLP-1 analogue monomer:

[0052] 1) Synthesis: The Fmoc method is used to implement the synthesis method step by step according to the following steps:

[0053] a) Fmoc-Arg-resin is obtained by coupling amino resin solid phase carrier and Fmoc protected arginine in the presence of activator system;

[0054] b) Connect amino acids in the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain N-terminal Fmoc-protected and side chain protected peptide-resin conjugates; the amino acids with side chains take the following protective measures: tryptophan with tert-butoxy Carbonyl (Boc), oxy-tert-butyl (OtBu) for glutamic acid, tert-butoxycarbonyl (Boc) for lysine, trityl (Trt) for glutamine, tert-butyl for tyrosine (tBu) ), Serine uses trityl (Trt) or tert-butyl (tBu), aspartic acid uses oxy-tert-butyl (OtBu), threonine uses tert-butyl (tBu), histidine uses trityl Group (T...

Embodiment 2

[0070] Example 2 Preparation of N-terminal acylated GLP-1 analog dimer

[0071] 1) Synthesize N-terminal Fmoc-protected and side chain protected peptide-resin conjugates according to the monomer synthesis method in Example 1;

[0072] 2) The N-terminal Fmoc protective group is removed by conventional methods, the resin-peptide conjugate is suspended in an appropriate amount of pyridine, and an appropriate molar ratio of acetic anhydride or trifluoroacetic anhydride is added, mixed and placed to obtain N-terminal histidine Chemical peptide-resin conjugate;

[0073] 3) Cleavage according to the method in Example 1 to obtain the crude peptide, purify and freeze-dry to obtain the monomer target peptide;

[0074] 4) Prepare the dimer according to the method in Example 1.

[0075] The GLP-1 analog dimer formed by the monomers of the following sequence was prepared according to the above method:

[0076] The GLP-1 analog dimer 3-3 formed by SEQ ID NO 3 and SEQ ID NO 3,

[0077] GLP-1 analog d...

Embodiment 3

[0081] Example 3 Preparation of GLP-1 analogue monomer and dimer

[0082] A. Preparation of GLP-1 analogue monomer:

[0083] 1) Synthesis: The Fmoc method is used to implement the synthesis method step by step according to the following steps:

[0084] a) Fmoc-Ala-resin is obtained by coupling amino resin solid phase carrier and Fmoc protected glycine in the presence of activator system;

[0085] b) Connect amino acids in the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain N-terminal Fmoc-protected and side chain protected peptide-resin conjugates; the amino acids with side chains take the following protective measures: tryptophan with tert-butoxy Carbonyl (Boc), oxy-tert-butyl (OtBu) for glutamic acid, tert-butoxycarbonyl (Boc) for lysine, trityl (Trt) for glutamine, tert-butyl for tyrosine (tBu) ), Serine uses trityl (Trt) or tert-butyl (tBu), aspartic acid uses oxy-tert-butyl (OtBu), threonine uses tert-butyl (tBu), histidine uses trityl Group (Tr...

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Abstract

The invention provides a monomer peptide of a glucagon-like peptide-1 analogue. The monomer peptide is represented by a general formula 1: Z<1>HAX<1>GTFTSDVSSYLE X<2>QAAKEFIAWLVKGRGCAX<3>, wherein Z<1> is H, acetyl or trifluoroacetyl; X<1> is Met, Leu, Pro, Phe, or Tyr; X<2> is Gly, Glu, or Aib (2-aminoisobutyric acid); and X<3> is NH<2> or H. The invention also provides a dimer formed by the monomer peptide, a preparation method of the dimer and applications of the dimer in preparing medicines. The dimer of the GLP-1 analogue monomer peptide provided by the invention has an obvious hypoglycemic effect, and the half-life in vivo can reach 12-72 hours or above, so that the problem of short half-life of natural GLP-1 is overcome and compliance of clinical application can be greatly improved.

Description

Technical field [0001] The present invention relates to the technical field of medicine, in particular to a glucagon-like peptide-1 (GLP-1) analog with long-acting effect and its dimer. The present invention also relates to the application of the GLP-1 analog dimer in the preparation of medicines for treating and / or preventing diabetes, obesity and Alzheimer's disease. Background technique [0002] Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone, which is mainly synthesized in the L cells of the terminal jejunum, ileum and colon, and released into the circulation in response to meals. GLP-1 (7-36, 7-37) is the main active form of GLP-1 in the systemic circulation. It controls blood glucose through complex mechanisms, including the secretion of insulin and glucagon, gastric emptying, and peripheral insulin regulation. The hypoglycemic effect of GLP-1 (7-36, 7-37) is glucose-dependent, can avoid hypoglycemia, and has the effect of inhibiting the apoptosis of islet β-cells...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04A61P25/28
CPCA61K38/00C07K14/605Y02P20/55
Inventor 赵娜夏韩英梅王玉丽夏广萍
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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